This award will support the training and career development of a junior investigator in cardiovascular epidemiology and pharmacogenomics, with special emphasis on the role of catechol-O-methyltransferase (COMT) in cardiovascular disease (CVD) and preventive treatment. Despite significant strides in prevention and management, CVD remains a leading cause of death in the United States. Pharmacogenomics, the study of how an individual's genome affects their treatment response, has expanded our understanding of the pathophysiology and treatment of CVD. However, gene-drug interactions have been difficult to assess in epidemiologic and clinical studies, in part because of the extraordinarily large sample sizes required for genome-wide association studies of these interactions and lack of strong candidate genes. COMT, which encodes a key enzyme in degradation of catecholamines including epinephrine, norepinephrine and catechol estrogen, is a strong candidate gene with plausible physiological links to both CVD and drug metabolism. COMT rs4680 is a well-studied and extremely common genetic polymorphism which results in a 3-4 fold reduction in enzymatic activity. The COMT genetic variant encoding the low-activity form of the enzyme, was associated with increased CVD risk and higher levels of triglycerides, systolic blood pressure and hemoglobin A1c in the Women's (Genome) Health Study (N=23,294). Interestingly over the 10 years of the study, women homozygous for the COMT low-activity genotype randomized to aspirin treatment had lower rates of CVD. Conversely, COMT high-activity homozygous women randomized to aspirin had higher CVD rates compared to placebo. Given the widespread use of aspirin for prevention of CVD, and the high prevalence of COMT rs4680 genetic variants, it is imperative that we understand the generalizability, mechanism and impact of the COMT locus itself and drugs that may share common molecular pathways and networks with it. This translational research proposal addresses these gaps by: 1) an epidemiologic study of COMT association with incidence of subclinical and clinical CVD in a multi-ethnic cohort; 2) using large-scale gene-expression and pharmacogenomic data to elucidate COMT molecular pathways and interacting drugs, and 3) conducting clinical studies to examine effects of these drugs on ex-vivo and in-vivo platelet function. As an emerging genetic locus with pleiotropic CVD and drug interaction effects, COMT is an excellent model system to probe the multiple molecular pathways and networks involved in cardiovascular function, disease and treatment and thus guide the development of novel strategies to attenuate CVD risk, and a promising example in which to develop personal expertise in cardiovascular epidemiology, systems biology, clinical trials, and other key career development milestones. (End of Abstract)